tbuckley/cabot-search huggingface dataset:
Abstract C042: Deletion of Gα13 promotes inflammation in the KPC mouse model of pancreatic cancer
Authors: Mario A. Shields, Anastasia E. Metropulos, Christina Spaulding, Thao ND Pham, Hidayatullah G. Munshi
Journal: Cancer Research (2022)

Abstract G protein-coupled receptor (GPCR) signaling regulates many aspects of tumor biology, including inflammation, angiogenesis, and metastasis. However, the tumor-specific functions of G proteins, immediate downstream signaling partners of GPCRs, are not well understood. Counter to previous reports in epithelial cancer cell lines, we recently showed that Gα13, a member of the G12 family of heterotrimeric G proteins, is a tumor suppressor in the genetically engineered KPC (Pdx1-Cre; KrasG12D/+; Tp53R172H/+) mouse model of pancreas cancer (Shields et al., Cell Rep, 2022). Mechanistically, we found that Gα13 loss increases mTOR signaling in mouse and human pancreas tumors and that Gα13-deficient tumors are susceptible to rapamycin. We now show that Gα13 loss in the KPC mouse model is also associated with increased expression of inflammatory cytokines. Moreover, loss of Gα13 also promotes NF-κB signaling and inflammatory cytokines expression in cerulein-driven pancreatitis. Consistently, we find that loss of Gα13 increases the recruitment of macrophages and promotes acinar-ductal metaplasia in cerulein-driven pancreatitis. In our ongoing studies, we are evaluating the role of mTOR signaling in mediating the increased inflammation seen following the loss of Gα13 in our mouse models. Together, our studies show that the tumor-suppressive function of Gα13 is related to the regulation of mTOR signaling and inflammation in pancreas cancer. Citation Format: Mario A. Shields, Anastasia E. Metropulos, Christina Spaulding, Thao ND Pham, Hidayatullah G. Munshi. Deletion of Gα13 promotes inflammation in the KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C042.
Abstract A079: The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses
Authors: Ahmed Ahmed, Tariq Arshad, Stephen Neidle
Journal: Cancer Research (2022)

Abstract The human genome contains multiple sites of quadruplex (G4) arrangements, with over-representation in promoter regions of many oncogenes. Small molecule G4 stabilization down-regulates the transcription of these genes, leading to selective inhibition of cancer cell growth and anti-tumor activity. We have developed a number of novel G4-binding small molecules. QN-302, the most potent, has significant in vivo activity in animal models for pancreatic cancer and is currently in pre-clinical development with Qualigen Therapeutics. The effects of QN-302 have been examined on (1) a panel of cardiac function receptors, (2) heart rate in vivo, and (3) on the histopathology of organs from treated animals. QN-302 was initially screened in a series of in vitro industry-standard CEREP receptor binding assays. The few apparent indications of significant receptor binding were examined in vivo by means of ELISA assays. Cardiac function was examined using a cardiac heart-beat monitor attached to animals treated with QN-302 and compared to animals dosed with a vehicle control. QN-302 gave negative results in CEREP assays, apart from micromolar inhibition of acetylcholinesterase (ACE) and muscarinic (MUSC) receptors. There was no significant hERG receptor inhibition. There was no significant inhibition of ACE and MUSC receptors in vivo. Heart rate experiments, run at both the proposed therapeutic dose of 1mg/kg and at elevated levels, did not show significant deviations from values for the vehicle control arm. Histopathology of heart, liver and brain tissues from QN-302 treated animals, did not show any deleterious effects from the drug. The lack of effects on ACE and MUSC receptors in vivo, together with the absence of effects on heart, liver and brain tissue from treated animals and the normality of heart rate during treatment, demonstrate that treatment of MIA-Paca2 tumor-bearing mice with QN-302 does not have a cardio-, nephro- or neurotoxic burden at therapeutic doses. QN-302 is bio-available at therapeutic doses and is currently in pre-clinical development with Qualigen Therapeutics Inc Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A079.
Abstract C045: CA19-9-mediated remodeling of the pancreatic tumor microenvironment
Authors: Jasper Hsu, Sejin Chung, Angelica E. Rock, Shira R. Okhovat, Dannielle D. Engle
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is an intractable common malignancy with a pro-tumorigenic and immunosuppressive microenvironment (ME) that often limits treatment efficacy. The glycan CA19-9 is used to follow treatment response in PDA patients, but its functional role in PDA remained unknown until recently because rodents lack this carbohydrate. CA19-9 elevation in a KRAS-mutant background promotes rapid progression to invasive carcinoma and induces ME remodeling in mice. The tumor ME includes cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) that contribute to desmoplasia, immunosuppression, and therapeutic resistance. All prior work investigating the tumor ME in PDA mouse models was performed in a CA19-9 negative context, potentially missing a key element of PDA biology. Elevation of CA19-9 in mice caused expansion of both CAFs and TAMs, but the mechanisms by which CA19-9 contributes to ME remodeling remains largely unknown. We aim to uncover the direct and indirect mechanisms of CA19-9-mediated ME remodeling. We identified CA19-9 modified ligands by immunoprecipitation and mass spectrometry that may contribute to reprogramming of the PDA ME. In addition to exploring changes in abundance, localization, and protein interactions, we will functionally characterize these candidate effectors via CRISPR ablation and antibody blockade using a novel Macrophage, Organoid, and Fibroblast (MOrF) co-culture platform. MOrF co-cultures can be sustained for at least 10 days in defined media conditions and enable compartment specific delineation of paracrine and juxtacrine signals. While CA19-9 modification may play a direct role in stromal remodeling, we also investigate effectors that are altered in response to CA19-9 elevation. CA19-9 induction in KRAS-mutant organoid mono-cultures increased gene expression of IL1α, CSF1,and TGFβ. In addition, CA19-9 expression increased gene set enrichment of inflammatory programs inorganoid mono-culture and led to increased expression of CAF and TAM differentiation programs in MOrF co-culture. These results are being validated as discussed above as well as by evaluation in vivo in CA19-9 positive and negative syngeneic orthotopic transplantation and autochthonous genetically engineered mouse models using scRNA-seq, pharmacologic and genetic perturbation, as well as other approaches. Using these orthogonal approaches, we will identify the mechanisms by which CA19-9 directly and indirectly contributes to PDA ME remodeling and ultimately, contributes to treatment response in the future. Citation Format: Jasper Hsu, Sejin Chung, Angelica E. Rock, Shira R. Okhovat, Dannielle D. Engle. CA19-9-mediated remodeling of the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C045.
Abstract C067: Understanding the tumor extrinsic role of oncogenic Kras in pancreatic cancer
Authors: Monica E. Bonilla
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year survival rate of 10.8%. Most patients present with locally advanced or metastatic disease which is refractory to therapy. Even when surgical resection is possible, relapse is frequent. Thus, there is a need to understand relapse and treatment resistance in pancreatic cancer to develop more effective treatments. Oncogenic KRAS is a driving mutation in PDA. Work in mouse models demonstrated that oncogenic KRAS drives the initiation of pancreatic cancer. Further, our group and others showed that oncogenic KRAS is required for the maintenance of precursor lesions as well as advanced and metastatic disease. We have recently investigated the extrinsic effects of oncogenic KRAS in precursor lesions of pancreatic cancer; we found that oncogenic KRAS drives reprogramming of precursor associated fibroblasts (PAFs or pre-cancer associated fibroblasts; pre-CAFs) to express immunosuppressive cytokines. The extrinsic effects of oncogenic KRAS in advanced disease have so far not been fully elucidated. In brief, we orthotopically transplanted iKRAS cells —derived from a mouse model of inducible and reversible oncogenic KRAS expression— in the pancreas of syngeneic mice. We then administered Doxycycline (DOX) to induce tumor growth. Once tumors had reached the desired size, we split the mice in two cohorts, one that was kept of DOX and one that was taken off DOX. All the animals were sacrificed 3 days later, tumors were dissected and processed for single cell RNA sequencing. We performed bioinformatics analysis on the tumors using the SEURAT pipeline, and mapped cellular composition, changes in gene expression and predicted interactions regulated by oncogenic KRAS. Interestingly, we discovered that several immunosuppressive pathways are alleviated upon KRAS inactivation, and CD8+ T cell infiltration increases. We and others have described resistance to oncogenic KRAS and eventual relapse in the iKRAS mouse model. Further, clinical data from the first KRAS inhibitors tested in clinical trials (G12C mutant-specific inhibitors in lung adenocarcinoma) similarly revealed initial response followed, in most cases, by relapse. We are thus interested in studying the mechanisms of KRAS inhibition resistance and specifically determine whether immunotherapy can be combined with KRAS inactivation to prevent relapse. Citation Format: Monica E. Bonilla. Understanding the tumor extrinsic role of oncogenic Kras in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C067.
Abstract B005: Polycyclic aromatic hydrocarbons and pancreatic cancer: An analysis of blood biomarker PheT as an exposure identifier
Authors: Sierra Nguyen, Heather Carlson, Andrea Yoder, William R. Bamlet, Ann L. Oberg, Gloria M. Peterson, Steven Hecht, Rick Jansen
Journal: Cancer Research (2022)

Abstract Exposure to polycyclic aromatic hydrocarbons (PAHs), a byproduct of incomplete combustion, and its effects on the development of cancer needs further evaluation. Recent studies have analyzed the relationship between PAHs and tobacco or dietary intake in the form of processed foods and smoked/well-done meats. This study aims to assess the association of a blood biomarker and metabolite of PAHs, r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), selected metabolism SNPs, and pancreatic cancer. Demographics, food-frequency data, SNPs, treatment history and levels of PheT in plasma were collected from 400 participants (202 cases and 198 control) and evaluated based on pancreatic adenocarcinoma diagnosis. A two-stage analysis was completed to identify 1) SNPs that were significantly associated with pancreatic cancer and 2) Dietary intake and PheT variables significantly associated with pancreatic cancer. A univariate analysis for variables with OR≠1 and p-value &amp;lt; 0.05 suggests significant relationship with pancreatic cancer and were carried forward to a multiple regression model for either food items or SNPs. Backward stepwise selection was used to eliminate non-significant variables. A collection of 5 SNPs were observed to form several of the most significant (adjusted p-value &amp;lt;0.05) interaction pairs across different SNP models. These were rs566979 (gene: CAT), rs28540420 (gene: PTGER4), rs12029406 (gene: none), rs730368 (gene: PTGER4), and rs3181077 (gene: CCR1). A final multiple regression model combined the significant food items and SNPs. Final significant factors associated with pancreatic cancer after backward selection included: Type 2 Diabetes [7.66 (3.46, 17.76)], corrected percent recovered version of the PAH (cPheT) [1.03 (1.02, 1.05)], very well done red meat [0.90 (0.84, 0.96)], recessive(rs12203582) [3.58 (1.50, 8.83)], recessive(rs56679) [0.25 (0.06, 0.80)], overdominant(rs3784605) [3.42 (1.81, 6.66)], overdominant(rs721430) [0.42 (0.21, 0.83)]. Of note by design, the level of smoking did not differ between our cases and controls. This study provides evidence that a metabolite PheT could be a biomarker of pancreatic cancer independent of dietary intake, smoking, and select metabolism SNPs. Citation Format: Sierra Nguyen, Heather Carlson, Andrea Yoder, William R. Bamlet, Ann L. Oberg, Gloria M. Peterson, Steven Hecht, Rick Jansen. Polycyclic aromatic hydrocarbons and pancreatic cancer: An analysis of blood biomarker PheT as an exposure identifier [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B005.
Abstract B052: Uncovering the lineage of chemosensory cells in the progression of pancreatic cancer
Authors: Daniel Salas-Escabillas, Howard Crawford, Megan Hoffman
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is predicted to become the second leading cause of cancer-related death in 2025 and has a 5-year survival rate of only 11%. Progression of the pancreatic disease is in part driven by the transdifferentiation of acinar cells into metaplastic ducts in the pancreas. Metaplastic tuft cells (MTCs) are a specialized subset of the metaplastic epithelium that has the potential to drive tumor progression through communication with the microenvironment and modulate PDA progression. Also known as solitary chemosensory cells, tuft cells were first discovered in rodent luminal surfaces, including the nose, stomach, intestine, and bladder, more than 60 years ago. They are characterized by the “tuft” of microvilli reaching into the lumen and, only recently, have studies started to determine the role of normal tuft cells in different organs. These studies determined that tuft cells have different roles depending on the organ in which they reside. Tuft cells are found in several different organs during normal development; however, studies have shown that tuft cells are not present in a normal pancreas. MTCs are only present in the pancreas in PanINs during PDA progression in both humans and mice. Furthermore, the population of MTCs in the pancreas disappears as PDA progresses into invasive carcinoma when using canonical markers of tuft cells. We know little about the role of MTCs in the pancreas, but prior studies have suggested their role as a progenitor cell during PDA. However, these studies do not exclusively mark MTCs during their genesis in a progressive model of PDA due to a lack of a mouse model as well as the complexity of culturing them ex vivo. We have generated a unique mouse model to drive lineage tracing of MTCs during PDA, and I have preliminary data to suggest that MTCs are not disappearing as PDA progresses but can transdifferentiate into another cell type that is correlated with lower survival in patients. Citation Format: Daniel Salas-Escabillas, Howard Crawford, Megan Hoffman. Uncovering the lineage of chemosensory cells in the progression of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B052.
Abstract C023: A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer
Authors: Gauri Mirji, Alison Worth, Sajad Bhat, Mohamed Sayed, Toshitha Kannan, Aaron Goldman, Hsin-Yao Tang, Qin Liu, Noam Auslander, Chi Dang, Mohamed Abdel-Mohsen, Andrew Kossenkov, Ben Stanger, Rahul Shinde
Journal: Cancer Research (2022)

Abstract The composition of the gut microbiome controls innate and adaptive immunity and has emerged as a key regulator of tumor growth and the success of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. We found that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) enhances anti-tumor immunity to PDAC. Delivery of TMAO given intraperitoneally or via dietary choline supplement to PDAC-bearing mice reduces tumor growth and is associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO signals through potentiating type-I interferon (IFN) pathway and confers anti-tumor effects in a type-I IFN dependent manner. Notably, delivering TMAO-primed macrophages alone produced similar anti-tumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Finally, the levels of trimethylamine (TMA)-producing bacteria and of CutC gene expression correlate with improved survivorship and response to anti-PD1 in cancer patients. Together, our study identifies the gut microbial metabolite TMAO as an important driver of anti-tumor immunity and lays the groundwork for new therapeutic strategies. Citation Format: Gauri Mirji, Alison Worth, Sajad Bhat, Mohamed Sayed, Toshitha Kannan, Aaron Goldman, Hsin-Yao Tang, Qin Liu, Noam Auslander, Chi Dang, Mohamed Abdel-Mohsen, Andrew Kossenkov, Ben Stanger, Rahul Shinde. A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C023.
Abstract IA010: Meeting the challenge of pancreatic cancer
Authors: Philip A. Philip
Journal: Cancer Research (2022)

Abstract Approximately one third of patients (pts) with pancreatic adenocarcinoma (PDA) present with locally advanced unresectable disease (LAPC). Majority of pts with LAPC have micrometastatic disease at presentation. However, median survival times exceed those of pts with radiologically visible metastases and is currently around 14-16 months (versus less than 1 year). Initial treatment strategies in LAPC focused on radiation that did not improve survival. With improvements in systemic therapies, current treatments of LAPC are based on cytotoxic combinations similar to ones used in metastatic PDA. However, benefits of cytotoxic therapy remain very modest. Unfortunately, the development of systemic therapy for PDA was plagued by repeated failures of randomized clinical trials of a range of targeted and other agents. In recent years, we exponentially advanced knowledge of PDA’s molecular biology and are attempting to learn from our clinical failures. One thing that stood out, with very few exceptions, is lack of success in single target/pathway strategies, especially in the absence of predictive biomarkers and lack of targetable “driver” mutations. Immune checkpoint inhibitors were ineffective unlike successes in other cancers. Focus has therefore shifted to rational strategies based on biology that defines phenotype along with ongoing attempts to refine molecular characterizations of PDA. Major research strategies include targeting the stroma to enhance drug delivery (e.g., CEND-1), reversing the immune suppressive microenvironment (combinatorial immunotherapy), exploiting DNA repair defects (e.g., BRCA mutations), and most importantly tackling KRAS oncogene. KRASG12C, KRASwt, BRCAmutated, and microsatellite instability provide additional treatment opportunities in up to 10% of PDA patients. The goal of new therapy developments in LAPC must address the locoregional morbidity of the primary tumor with the ultimate goal of prolonging survival. Examples of ongoing research in locoregionally directed therapy include ablative radiation and tumor treating fields (TTF) that attempt to control its growth, reduce the tumor bulk, and improve possibilities of tumor resection. As our systemic therapies improve, locoregional therapy becomes more relevant. Improvements in molecular classifications of PDA, refinements in the use of organoids to predict drug and radiation effect, and use of liquid biopsies are examples of measures that will provide foundations for personalized treatment approaches. Collectively, we have endless opportunities for translational research based on advances in PDA’s basic science and our experiences from the many “negative” clinical trials. Citation Format: Philip A. Philip. Meeting the challenge of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA010.